Submissions for variant NM_000277.3(PAH):c.568G>A (p.Val190Met)

dbSNP: rs281865441

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000106360	SCV000886581	uncertain significance	Phenylketonuria	2018-12-10	reviewed by expert panel	curation	The c.568G>A (p.Val190Met) variant in PAH has not been reported in the literature to our knowledge. The reference from BioPKU (Namour B, Jeannesson E, Chery C, Gueant JL, Feillet F, 2013) cannot be located. This variant is absent from ExAC, gnomAD, 1000G, and ESP. It is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.836. Another variant at this amino acid (p.V190G) is interpreted as pathogenic by the PAH VCEP. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000106360	SCV003316864	likely pathogenic	Phenylketonuria	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 190 of the PAH protein (p.Val190Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 32668217). ClinVar contains an entry for this variant (Variation ID: 120279). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAH protein function. This variant disrupts the p.Val190 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9452062, 11486900, 17502162, 26666653; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Inserm U 954, Faculté de Médecine de Nancy	RCV000106360	SCV000143860	probable-pathogenic	Phenylketonuria		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.